Cardiovascular disease (CVD) is the leading cause of death in the western world. However, why some individuals with identical risk factor profiles will go on to develop CVD, whereas others will not, is simply not understood. One explanation is that CVD is a multifactorial disorder that involves both environmental and genetic factors. Recent studies on CVD susceptibility and resistance support the concept of groups of genes being involved in disease susceptibility - and while important in advancing the understanding of gene "groups" that may be involved in influencing individual biological responses to an environmental challenge, they do not address the underlying issue of why these differences exist, nor how they might have developed. In this respect, none of the current studies has considered the potential role of the "other" eukaryotic genome, the mitochondrial DNA (mtDNA), or the mitochondrion, and the possibility that prehistoric selection factors that influenced mtDNA genetic selection and thus, mitochondrial-nuclear interaction, today influence individual CVD susceptibility. This proposal tests the hypothesis that mitochondrial function and genetics are important factors in influencing CVD susceptibility by determining the impact of i) mitochondrial function on vascular function;ii) the roles of mitochondrial and nuclear genetic backgrounds on vascular function and gene expression, and;iii) mitochondrial genetic ancestry on vascular function in humans. Preliminary studies are provided that show: i) mice known to be resistant to CVD have genetically distinct mitochondrial DNA (mtDNA) haplotypes and function compared to those with increased CVD susceptibility;ii) CVD resistant mice have lower levels of oxidative stress, mitochondrial damage, membrane potential, and increased sensitivity to acetylcholine-induced endothelium dependent vasorelaxation compared to CVD susceptible mice;and, iii) "mitochondrial - nuclear exchange" mice show that vascular function segregates with mtDNA haplotype. These studies will provide novel insights regarding the role of the mitochondrion in influencing individual vascular function, and therefore, impacting disease susceptibility. Furthermore, they have the potential for revealing a mechanistic relationship of mitochondrial - nuclear "compatibility" as an important determinant and paradigm for environmental - genetic interaction and human disease susceptibility. The University of Alabama at Birmingham (UAB) is Alabama's largest employer, with more than 18,000 faculty and staff at the university and in the health system, and is responsible for 52,900 full-time equivalent jobs withi the university and the community. Eight in every 100 jobs in the Birmingham area, and 2.8 jobs in every 100 jobs in Alabama, are related to UAB. UAB's overall economic impact in the Birmingham metro area exceeds $3 billion annually. Consistent with ARRA goals, this application will create or retain 3.17 full-time equivalent jobs.